6 alkoxy-4-pyrimidinyl bis-sulfonamides

ABSTRACT

The present invention relates to novel bis-sulfonamides represented, for example, by formula I below and a pure diastereomer, a mixture of diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates and meso-forms and a pharmaceutically acceptable salt thereof, wherein R 1  represents aryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; or heteroaryl-lower alkyl; and R 2  represents lower alkyl; trifluoromethyl; lower alkoxy-lower alkyl; lower alkenyl; lower alkynyl; aryl; aryl-lower alkyl; aryl-lower alkenyl; heterocyclyl; heterocyclyl-lower alkyl; heteroaryl; heteroaryl-lower alkyl; cycloalkyl; or cycloalkyl-lower alkyl. The present invention also relates to a process for manufacturing those compounds, pharmaceutical compositions containing one or more of those compounds as endothelin antagonists, and a method of treating a subject having a disorder involving endothelin with the compounds of                    
     the invention.

The present invention relates to novel bis-sulfonamides of the generalformula I and their use as active ingredients in the preparation ofpharmaceutical compositions. The invention also concerns related aspectsincluding processes for the preparation of the compounds, pharmaceuticalcompositions containing one or more compounds of the general formula Iand especially their use as endothelin antagonists.

Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides producedand active in almost all tissues (Yanagisawa M et al.: Nature (1988)332:411). Endothelins are potent vasoconstrictors and importantmediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621). They participate inbronchoconstriction and regulate neurotransmitter release, activation ofinflammatory cells, fibrosis, cell proliferation and celldifferentiation (Rubanyi G M et al.: Pharmacol Rev (1994) 46:328).

Two endothelin receptors have been cloned and characterized in mammals(ET_(A), ET_(B)) (Arai H et al.: Nature (1990) 348:730; Sakurai T etal.: Nature (1990) 348:732). The ET_(A) receptor is characterized byhigher affinity for ET-1 and ET-2 than for ET-3. It is predominant invascular smooth muscle cells and mediates vasoconstricting andproliferative responses (Ohlstein E H et al.: Drug Dev Res (1993)29:108). In contrast, the ET_(B) receptor has equivalent affinity forthe 3 endothelin isopeptides and binds the linear form of endothelin,tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991)178:248). This receptor is located in the vascular endothelium andsmooth muscles, and is also particularly abundant in lung and brain. TheET_(B) receptor from endothelial cells mediates transient vasodilatorresponses to ET-1 and ET-3 through the release of nitric oxide and/orprostacyclin whereas the ET_(B) receptor from smooth muscle cells exertsvasoconstricting actions (Sumner M J et al.: Brit J Pharmacol (1992)107:858). ET_(A) and ET_(B) receptors are highly similar in structureand belong to the superfamily of G-protein coupled receptors.

A pathophysiological role has been suggested for ET-1 in view of itsincreased plasma and tissue levels in several disease states such ashypertension, sepsis, atherosclerosis, acute myocardial infarction,congestive heart failure, renal failure, migraine and asthma. As aconsequence, endothelin receptor antagonists have been studiedextensively as potential therapeutic agents. Endothelin receptorantagonists have demonstrated preclinical and/or clinical efficacy invarious diseases such as cerebral vasospasm following subarachnoidhemorrhage, heart failure, pulmonary and systemic hypertension,neurogenic inflammation, renal failure and myocardial infarction.

Today, no endothelin receptor antagonist is marketed yet, several are inclinical trials. However, these molecules possess a number of weaknessessuch as complex synthesis, low solubility, high molecular weight, poorpharmacokinetics, or safety problems (e.g. liver enzyme increases).Furthermore, the contribution of differential ET_(A)/ET_(B) receptorblockade to the clinical outcome is not known. Thus, tailoring of thephysicochemical and pharmacokinetic properties as well as theselectivity profile of each antagonist for a given clinical indicationis mandatory. We have discovered a new class of bis-sulfonamidecompounds of the structure below and found that they allow the specifictailoring described above.

The inhibitory activity of the compounds of formula I on endothelinreceptors can be demonstrated using the test procedures describedhereinafter:

For the Evaluation of the Potency and Efficacy of the Compounds of theGeneral Formula I the Following Tests Were Used

1) Inhibition of Endothelin Binding to Membranes from CHO Cells CarryingHuman ET Receptors:

For competition binding studies, membranes of CHO cells expressing humanrecombinant ET_(A) or ET_(B) receptors were used. Microsomal membranesfrom recombinant CHO cells were prepared and the binding assay made aspreviously described (Breu V., et al, FEBS Lett 1993; 334:210).

The assay was performed in 200 uL 50 mM Tris/HCl buffer, pH 7.4,including 25 mM MnCl₂, 1 mM EDTA and 0.5% (w/v) BSA in polypropylenemicrotiter plates. Membranes containing 0.5 ug protein were incubatedfor 2 h at 20° C. with 8 pM [¹²⁵I]ET-1 (4000 cpm) and increasingconcentrations of unlabelled antagonists. Maximum and minimum bindingwere estimated in samples without and with 100 nM ET-1, respectively.After two h, the membranes were filtered on, filterplates containingGF/C filters (Unifilterplates from Canberra Packard S. A. Zürich,Switzerland). To each well, 50 uL of scintillation cocktail was added(MicroScint 20, Canberra Packard S. A. Zürich, Switzerland) and thefilter plates counted in a microplate counter (TopCount, CanberraPackard S. A. Zürich, Switzerland).

All the test compounds were dissolved, diluted and added in DMSO. Theassay was run in the presence of 2.5% DMSO which was found not tointerfere significantly with the binding. IC₅₀ was calculated as theconcentration of antagonist inhibiting 50% of the specific binding ofET-1. For reference compounds, the following IC₅₀ values were found:ET_(A) cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ET_(B)cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3.

The IC₅₀ values obtained with compounds of formula I are given in Table1

TABLE 1 IC₅₀[nM] Compound of Example ET_(A) ET_(B) Example 2 1960 1790Example 5 5560 356 Example 6 8300 420 Example 7 63.6 15.8 Example 8 160130 Example 10 67.2 193 Example 11 5110 4.3 Example 12 2120 73.3 Example13 885 69.2 Example 14 518 451 Example 15 1320 7.3 Example 16 261 24.5Example 17 1100 117 Example 18 209 1050 Example 21 881 21.8 Example 2376.1 52.7 Example 27 3634 995 Example 28 3709 1043 Example 29 1253 235Example 30 484 288 Example 31 409 735 Example 36f 478 1212 Example 36g121 93 Example 37 5683 604 Example 38 80 84 Example 39 1048 81 Example40 76 87 Example 41 4898 299 Example 42 587 99 Example 43 75 376 Example44 119 323 Example 45 251 336 Example 46 140 103 Example 49 1027 274Example 51 3450 182 Example 54 2407 603 Example 57 1625 208 Example 58724 447 Example 59 103 189 Example 60 1442 16 Example 61 92 183 Example62 443 163 Example 68 477 169 Example 70 282 2071 Example 71 508 231Example 72 153 279 Example 73 233 542 Example 74 531 934 Example 77 1855402 Example 78 627 5458 Example 79 37 >10000 Example 80 14.8 59.4Example 81 104 1240 Example 82 311 3510 Example 87 48.1 33.1 Example 8814.8 1.86 Example 89 1591 101 Example 90 86 4.1 Example 91 45.5 103Example 92 82.1 15 Example 93 22.2 3.86 Example 94 77.3 18.6

2) Inhibition of Endothelin-induced Contractions on Isolated Rat AorticRings (ET_(A) Receptors) and Rat Tracheal Rings (ET_(B) Receptors)

The functional inhibitory potency of the endothelin antagonists wasassessed by their inhibition of the contraction induced by endothelin-1on rat aortic rings (ET_(A) receptors) and of the contraction induced bysarafotoxin S6c on rat tracheal rings (ET_(B) receptors). Adult Wistarrats were anesthetized and exsanguinated. The thoracic aorta or tracheawere excised, dissected and cut in 3-5 mm rings. Theendothelium/epithelium was removed by gentle rubbing of the intimalsurface. Each ring was suspended in a 10 ml isolated organ bath filledwith Krebs-Henseleit solution (in mM; NaCl 115, KCl 4.7, MgSO₄ 1.2,KH₂PO₄ 1.5, NaHCO₃ 25, CaCl₂ 2.5, glucose 10) kept at 37° and gassedwith 95% O₂ and 5% CO₂. The rings were connected to force transducersand isometric tension was recorded (EMKA Technologies SA, Paris,France). The rings were stretched to a resting tension of 3 g (aorta) or2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c(trachea) were added after a 10 min incubation with the test compound orits vehicle. The functional inhibitory potency of the test compound wasassessed by calculating the concentration ratio, i.e. the shift to theright of the EC₅₀ induced by different concentrations of test compound.EC₅₀ is the concentration of endothelin needed to get a half-maximalcontraction, pA₂ is the negative logarithm of the antagonistconcentration which induces a two-fold shift in the EC₅₀ value.

The pA₂ values obtained with compounds of formula I are given in Table2.

TABLE 2 pA₂ value Compound of Example ET_(A) ET_(B) Example 7 6.08 7.15Example 10 6.73 5.9 Example 11 <5 7.46 Example 12 6.07 6.29 Example 157.39 Example 16 <5.5 7.46 Example 55 6.2 6.3 Example 59 6.61 5.58Example 60 7.3 Example 61 7.02 6.36 Example 70 6.05 Example 87 6.52Example 88 6.16 7.95

Because of their ability to inhibit the endothelin binding, thedescribed compounds can be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation orinflammation due to endothelin. Examples of such diseases arehypertension, coronary diseases, cardiac insufficiency, renal andmyocardial ischemia, renal failure, cerebral ischemia, dementia,migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portalhypertension and pulmonary hypertension. They can also be used foratherosclerosis, prevention of restenosis after balloon or stentangioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatichypertrophy, erectile dysfunction, hearing loss, amaurosis, chronicbronchitis, asthma, gram negative septicemia, shock, sickle cell anemia,glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis ofdiabetic complications, complications of vascular or cardiac surgery orafter organ transplantation, complications of cyclosporin treatment, aswell as other diseases presently known to be related to endothelin.

The compounds can be administered orally, rectally, parenterally, e.g.by intravenous, intramuscular, subcutaneous, intrathecal or transdermaladministration or sublingually or as ophthalmic preparation oradministered as aerosol. Examples of applications are capsules, tablets,orally administered suspensions or solutions, suppositories, injections,eye-drops, ointments or aerosols/nebulizers.

Preferred applications are intravenous, intramuscular, or oraladministrations as well as eye drops. The dosage used depends upon thetype of the specific active ingredient, the age and the requirements ofthe patient and the kind of application. Generally, dosages of 0.1-050mg/kg body weight per day are considered. The preparations withcompounds can contain inert or as well pharmacodynamically activeexcipients. Tablets or granules, for example, could contain a number ofbinding agents, filling excipients, carrier substances or diluents.

The present invention relates to bis-sulfonamides of the general formulaI,

wherein

R¹ represents aryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl;heteroaryl-lower alkyl;

R² represents lower alkyl; trifluoromethyl; lower alkoxy-lower alkyl;lower alkenyl; lower alkynyl; aryl; aryl-lower alkyl; aryl-loweralkenyl; heterocyclyl; heterocyclyl-lower alkyl; heteroaryl;heteroaryl-lower alkyl; cycloalkyl; cycloalkyl-lower alkyl;

R³ represents phenyl; mono-, di- or tri-substituted phenyl substitutedwith lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, amino,lower alkylamino, amino-lower alkyl, trifluoromethyl, trifluoromethoxy,halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl,lower alkanoyl, formyl; benzofuranyl; aryl; heteroaryl;

R⁴ represents hydrogen; halogen; trifluoromethyl; lower alkyl; loweralkyl-amino; lower alkyloxy; lower alkyl-sulfono; lower alkyl-sulfinyl;lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; loweralkyl-oxy-lower alkyl; hydroxy-lower alkyl-oxy-lower alkyl;hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl, amino;di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino;aryl; aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-loweralkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl;aryl-sulfinyl; heteroaryl; heteroaryl-oxy; heteroaryl-lower alkyl-oxy;heteroaryl-amino; heteroaryl-lower alkyl-amino; heteroaryl-thio;heteroaryl-lower alkyl-thio; heteroaryl-lower alkyl;heteroaryl-sulfinyl; heterocyclyl; heterocyclyl-lower alkyl-oxy;heterocyclyl-oxy; heterocyclyl-amino; heterocyclyl-lower alkyl-amino;heterocyclyl-thio; heterocyclyl-lower alkyl-thio; heterocyclyl-loweralkyl; heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl-oxy;cycloalkyl-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-loweralkyl-amino; cycloalkyl-thio; cycloalkyl-lower alkyl-thio;cycloalkyl-lower alkyl; cycloalkyl-sulfinyl;

R⁶ represents hydrogen; lower alkyl; cycloalkyl; heterocyclyl;heteroaryl; aryl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl;heteroaryl-lower alkyl; aryl-lower alkyl; lower alkoxy-lower alkyl;lower alkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; loweralkenyl; lower alkynyl;

n represents the numbers 2, 3, 4 and 5;

X represents oxygen; sulfur; NH; CH₂ or a bond;

and pure diastereomers, mixtures of diastereomers, diastereomericracemates, mixtures of diastereomeric racemates and the meso-forms andpharmaceutically acceptable salts thereof.

In the definitions of the general formula I—if not otherwise stated—theexpression lower means straight and branched chain groups with one toseven carbon atoms, preferably 1 to 4 carbon atoms. Examples of loweralkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl,methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy andtert.-butoxy. Lower alkylendioxy-groups are preferably methylen-dioxy,ethylen-dioxy, propylen-dioxy and butylen-dioxy-groups. Examples oflower alkanoyl-groups are acetyl, propanoyl and butanoyl. Loweralkenylen means e.g.vinylen, propenylen and butenylen. Lower alkenyl andlower alkynyl means groups like ethylen, propylen, butylen,2-methyl-propenyl, and ethinylen, propinylen, butinylen, pentinylen,2-methyl-pentinylen etc. Lower alkenyloxy means allyloxy, vinyloxy,propenyloxy and the like. The expression cycloalkyl means a saturatedcyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may besubstituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl,lower alkoxy-lower alkyl and lower alkenylen groups. The expressionheterocyclyl means saturated or unsaturated (but not aromatic) four,five-, six- or seven-membered rings containing one or two nitrogen,oxygen or sulfur atoms which may be the same or different and whichrings may be substituted with lower alkyl, amino, nitro, hydroxy, loweralkoxy, e.g. piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl,dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl,dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, pyrazolidinyl etc.and substituted derivatives of such rings with substituents as outlinedabove. The expression heteroaryl means six-membered aromatic ringscontaining one to four nitrogen atoms, benzofused six-membered aromaticrings containing one to three nitrogen atoms, five-membered aromaticrings containing one oxygen or one nitrogen or one sulfur atom,benzo-fused five-membered aromatic rings containing one oxygen or onenitrogen or one sulfur atom, five membered aromatic rings containig anoxygen and nitrogen atom and benzo fused derivatives thereof, fivemembred aromatic rings containing a sulfur and a nitrogen atom and benzofused derivatives thereof, five-membered aromatic rings containing twonitrogen atoms and benzo fused derivatives thereof, five memberedaromatic rings containing three nitrogen atoms and benzo fusedderivatives thereof or the tetrazolyl ring e.g. furanyl, thienyl,pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl,triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, oxazolyl,isoxazolyl, etc. whereby such rings may be substituted with lower alkyl,lower alkenyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy,trifluoromethoxy or trifluoromethyl. The expression aryl representsunsubstituted as well as mono-, di- or tri-substituted aromatic ringswith 6 to 10-carbon atoms like phenyl or naphthyl rings which may besubstituted with aryl, halogen, hydroxy, lower alkyl, lower alkenyl,lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyl-loweralkyl-oxy, lower alkenylen, lower alkylenoxy, lower alkylenoxy or loweralkylendioxy forming with the phenyl ring a five- or six-membered ring,hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkyl-loweralkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy,trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl,heterocyclyl, heteroaryl.

Especially preferred compounds are compounds of formula I wherein R³represents phenyl or mono-substituted phenyl substituted with loweralkyloxy, especially methoxy, X represents oxygen and n represents thenumbers 2 or 3.

A second group of especially preferred compounds of formula I are thecompounds wherein R³ represents phenyl or monosubstituted phenylsubstituted with lower alkyl, especially methyl, or lower alkoxy,especially methoxy, X represents a bond and n represents the numbers 2or 3.

The expression pharmaceutically acceptable salts encompasses eithersalts with inorganic acids or organic acids like hydrohalogenic acids,e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid,nitric acid, citric acid, formic acid, acetic acid, maleic acid,tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the likeor in case the compound of formula I is acidic in nature with aninorganic base like an alkali or earth alkali base, e.g. sodiumhydroxide, potassium hydroxide, calcium hydroxide etc. The compounds ofthe general formula I have one or more asymmetric carbon atoms and maybe prepared in form of optically pure enantiomers or diastereomers,mixtures of enantiomers or diastereomers, diastereomeric racemates,mixtures of diastereomeric racemates and also in the meso-form. Thepresent invention encompasses all these forms. Mixtures may be separatedin a manner known per se, i.e. by column chromatography, thin layerchromatography, HPLC, crystallization etc.

Because of their ability to inhibit the endothelin binding, thedescribed compounds of the general formula I and their pharmaceuticallyacceptable salts may be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation orinflammation due to endothelin. Examples of such diseases arehypertension, coronary diseases, cardiac insufficiency, renal andmyocardial ischemia, renal failure, cerebral ischemia, dementia,migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portalhypertension and pulmonary hypertension. They can also be used foratherosclerosis, prevention of restenosis after balloon or stentangioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatichypertrophy, erectile dysfunction, hearing loss, amaurosis, chronicbronchitis, asthma, gram negative septicemia, shock, sickle cell anemia,glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis ofdiabetic complications, complications of vascular or cardiac surgery orafter organ transplantation, complications of cyclosporin treatment, aswell as other diseases presently known to be related to endothelin.

These compositions may be administered in enteral or oral form e.g. astablets, dragees, gelatine capsules, emulsions, solutions orsuspensions, in nasal form like sprays or rectically in form ofsuppositories. These compounds may also be administered inintramuscular, parenteral or intraveneous form, e.g. in form ofinjectable solutions.

These pharmaceutical compositions may contain the compounds of formula Ias well as their, pharmaceutically acceptable salts in combination withinorganic and/or organic excipients which are usual in thepharmaceutical industry like lactose, maize or derivatives thereof,talcum, stearinic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquidpolyols etc. may be used. For the preparation of solutions and sirupse.g. water, polyols, saccharose, glucose etc. are used. Injectables areprepared by using e.g. water, polyols, alcohols, glycerin, vegetableoils, lecithin, liposomes etc. Suppositories are prepared by usingnatural or hydrogenated oils, waxes, fatty acids (fats), liquid orhalf-liquid polyols etc.

The compositions may contain in addition preservatives, stabilisationimproving substances, viscosity improving or regulating substances,solubility improving substances, sweeteners, dyes, taste improvingcompounds, salts to change the osmotic pressure, buffer, anti oxidantsetc.

The compounds of formula I may also be used in combination with one ormore other therapeutically useful substances e.g. α- and β-blockers likePhentolamine, Phenoxybenzamine, Atenolol, Propranolol, Timolol,Metoprolol, Carteolol etc.; Vasodilators like Hydralazine, Minoxidil,Diazoxide, Flosequinan etc.; Calcium-antagonists like Diltiazem,Nicardipine, Nimodipine, Verapamil, Nifedipine etc.; ACE-inhibitors likeCilazapril, Captopril, Enalapril, Lisinopril etc.; Potassium activatorslike Pinacidil etc. Angiotensin II antagonists; Diuretics likeHydrochlorothiazide, Chlorothiazide, Acetolamide, Bumetanide,Furosemide, Metolazone, Chlortalidone etc.; Sympatholitics likeMethyldopa, Clonidine, Guanabenz, Reserpine etc.; and other therapeuticswhich serve to treat high blood pressure or any cardiac disorders.

The dosage may vary within wide limits but should be adapted to thespecific situation. In general the dosage given in oral form shoulddaily be between about 3 mg and about 3 g, preferably between about 10mg and about 1 g, especially preferred between 5 mg and 300 mg, peradult with a body weight of about 70 kg. The dosage should beadministered preferably in 1 to 3 doses per day which are of equalweight. As usual children should receive lower doses which are adaptedto body weight and age.

Preferred compounds are compounds of formula II

wherein R¹, R², R⁴, R⁶ and n are as defined in formula I above,

and pharmaceutically acceptable salts of compounds of formula II.

Especially preferred compounds among the group of compounds of formulaII are those wherein R⁶ represents hydrogen or lower alkyl.

Also preferred are compounds of formula III

wherein R¹, R², R⁴ and R⁶ are as defined in formula I above,

and pharmaceutically acceptable salts of compounds of formula III.

Especially preferred compounds among the group of compounds of formulaIII are those wherein R⁶ represents hydrogen or lower alkyl.

Also preferred are compounds of formula IV

wherein R², R⁴ and R⁶ are as defined in formula I above and R⁵represents hydrogen, methyl or isopropyl,

and pharmaceutically acceptable salts of compounds of formula IV.

Especially preferred compounds among the group of compounds of formulaIV are those wherein R⁶ represents hydrogen or lower alkyl.

Another preferred group of compounds are compounds of formula V

wherein R⁵ is as defined in formula IV above, R² and R⁶ are as definedin formula I above, U and V represent nitrogen and W represents carbon,or U and V represent carbon and W represents nitrogen,

and pharmaceutically acceptable salts thereof.

Especially preferred compounds among the group of compounds of formula Vare those wherein R⁶ represents hydrogen or lower alkyl.

Another preferred group of compounds are compounds of formula VI

wherein R¹, R², R³, R⁴, R⁶ and n are as defined in formula I above,

and pharmaceutically acceptable salts of compounds of formula VI.

Especially preferred compounds among the group of compounds of formulaVI are those wherein R⁶ represents hydrogen or lower alkyl.

Another preferred group of compounds are compounds of formula VII

wherein R¹, R², R⁴, R⁶ and n are as defined in formula I above,

and pharmaceutically acceptable salts of compounds of formula VII.

Especially preferred compounds among the group of compounds of formulaVII are those wherein R⁶ represents hydrogen or lower alkyl.

Preferred compounds are:

p-tert.-butyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-(2-propanesulfonamido))-5-(o-methoxyphenoxy)2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido)5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-benzenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-thiophenesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-(1-propanesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

p-tert.-butyl-N-[6-(ethoxy-2-(1-butanesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-p-toluenesulfonamido)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]pyridine-2-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-methanesulfonamido)-5-(o-methoxyphenoxy)-2-methyl4-pyrimidinyl]pyridine-2-sulfonamide,

4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-methanesulfonyl-5-(o-methoxyphenoxy-pyrimidin-4-yl]-benzenesulfonamide,

5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,

5-i-propyl-N-[6-(2-(4-methylbenzene)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,

4-tert.-butyl-N-[6-(2-(2-propane)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide,

5-isopropyl-N-[6-(2-(2-thiophensulfonyl)-amino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,

5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,

5-isopropyl-N-[6-(2-propanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,

5-methyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,

5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds are

p-tert.-butyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

5-i.-propyl-N-[6-(ethoxy-2-thiophenesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,

5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,

5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide

5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide

4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide

4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide

4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide

4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide

5-i.-propyl-N-[6-(3-(propanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide

5-i.-propyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide

5-i.-propyl-N-[6-(3-(p-toluenesulfonylamino)-propoxy)-5(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide

and pharmaceutically acceptable salts thereof.

The invention also relates to a process for the manufacture of compoundsof the general formula I:

wherein R¹, R², R⁴, R⁶, X and n have the meaning given in formula Iabove,

which process comprises

a) for obtaining compounds wherein R⁶ represents hydrogen, reacting acompound of formula VIII

wherein R¹, R³,R⁴, X and n have the meaning given in formula I above,

with a compound of the formula Cl—SO₂—R², wherein R² has the meaninggiven in formula I above, or

b) by reacting a compound of formula IX

wherein R¹, R³, R⁴ and X have the meaning given in formula I above, witha compound of formula X

wherein R², R⁶ and n have the meaning given in formula I above,

and, as the case may be, resolving a compound with one or more opticallyactive carbon atoms into pure enantiomers or diastereomers, mixtures ofenantiomers or diastereomers, diastereomeric racemates, or into themeso-form in a manner known per se.

and, if desired, converting a compound of formula I obtained into apharmaceutically acceptable salt in a manner known per se.

The above process may be described in more detail as follows:

The compounds of the general formula I of the present invention whereinR⁶ represents hydrogen, are prepared according to the general sequenceof reactions outlined in Scheme 1 below, wherein R¹,R²,R³,R⁴ and n areas defined in formula I above. For simplicity and clarity reasons SchemeI only describes part of the synthetic possibilities which lead tocompounds of formula I. The literature references given in brackets [ ]are set forth at the end of this paragraph. The amidines 2 weresynthesized applying standard methodology [1] by reaction of theappropriate nitrile 1 either with sodium methylate in methanol followedby addition of ammonium chloride or by reaction with lithiumhexamethyldisilazane followed by addidion of hydrochloric acid ini-propanol. The 2-substituted malonic esters 4 were prepared accoring topublished procedures [1] by reacting dimethylchloromalonate (3) with theappropriate alcohol 5 in acetone and potassium carbonate as base. Thecompounds 4 were dissolved in methanol and sodium methylate was addedand stirring was continued for about 30 min followed by the addition ofan amidine derivative 2. Stirring at ambient temperature was continuedfor another 8 h. After acidic work up the 4,6-dihydroxypyrimidines 6could be isolated in yields of 70 to 90% [2]. Compounds 6 or thetautomeric form thereof were transformed into the dichloroderivatives 7with phosphorous oxychloride at elevated temperatures (60-120° C.) inyields of 40 to 75% [3]. In some cases better yields were obtained byaddition of PCl₅ or benzyl-triethylammoniumchloride. The dichlorides 7were reacted with an excess of the appropriate sulfonamide potassiumsalt 9 (prepared according to standard methodology from thesulfochlorides 8) in DMSO at room temperature to give the pyrimidines 10in yields of 70 to 90% either after recrystallization from ethylacetate/diethylether or chromatography over silica gel with ethylacetate/heptane. The pyrimidine derivatives 10 are the centralintermediates which can be transformed to the desired final products bytwo different pathways. Depending on the nature of R¹, R³ and R⁴ thesuitable reaction sequence is chosen. The first possibility to transform10 into the final products 13 is by reaction with the1-hydroxy-ω-sulfonamido-alkyl-compounds 12 (prepared from theappropriate 1,ω-aminoalcohol 11 and the sulfochlorides 15 at roomtemperature in THF) in THF/DMSO=15/1 and potassium tert.-butylate asbase at elevated temperatures (60 to 120° C. in yields of 40 to 80%. Thesecond reaction sequence starts with the introduction of theoxy-alkyl-amino side chain by reaction of 10 with the appropriate1,ω-aminoalcohol 11 in THF/DMF=1/1 and sodium hydride as base to givecompounds 14 in yields of 50 to 70% after recrystallization. Thealkylamino functionality of 14 was then reacted by standard methodology[4] with the desired sulfochlorides 15 in methylene chloride and Hünig'sbase to give the target bis-sulfonamides 13 in yields of 40 to 75% afterrecrystallization from mixtures of methanol/acetonitrile and/or diethylether.

Compounds of general formula I wherein R¹, R², R³, R⁴, X and n are asdefined in general formula I above and wherein R⁶ is as defined ingeneral formula I above but does not represent hydrogen, can be preparedaccording to Scheme 2. For simplicity and clarity reasons, Scheme 2 onlydescribes part of the synthetic possibilities which lead to compounds offormula I. Compounds 16, prepared according to the description given inScheme 1 and [5], [6] are reacted with compounds 18 under the samereaction conditions given for the synthesis of compounds 13 to givecompounds 19 (which correspond to compounds of general formula I).Compounds 18 are obtained by reacting the aminoalcohol derivatives 17with the sulfochlorides 15 under the conditions described in Scheme 1.Compounds 17 are either commercially available or can be prepared bystandard procedures (reductive amination, alkylation etc) fromaminoalcohols or from the hydroxy protected aminoalcohols containing aprimary amino group.

[1] W. Göhring, J. Schildknecht, M. Federspiel; Chimia, 1996, 50,538-543

[2] W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G. Hirth, M.Müller, H. P. Wessel, H. Ramuz; Chimia, 1996, 50, 519-524 and referencescited there.

[3] W. Neidhart, V. Breu, K. Burri, M. Clozel, G. Hirth, U. Klinkhammer,T. Giller, H. Ramuz; Bioorg. Med. Chem. Lett., 1997, 7, 2223-2228. R. A.Nugent, S. T. Schlachter, M. J. Murphy, G. J. Cleek, T. J. Poel, D. G.Whishka, D. R. Graber, Y. Yagi, B. J. Keiser, R. A. Olmsted, L. A.Kopta, S. M. Swaney, S. M. Poppe, J. Morris, W. G. Tarpley R. C. Thomas;J. Med. Chem., 1998, 41, 3793-3803.

[4] J. March; Advanced Organic Chemistry, 4^(th) Ed., 1994, p. 499 andreferences cited there.

[5] EP 0 743 307 A1; EP 0 658 548 B1; EP 0 959 072 A1 (Tanabe Seiyaku)

[6] EP 0 633 259 B1; EP 0 526 708 A1; WO 96/19459 (F. Hofmann-LaRoche)

According to the procedures described in [5] and for Schemes 1 and 2compounds of the general formula I can also be prepared as displayed inScheme 3 below wherein R¹, R², R³, R⁴, R⁶, X and n are as defined ingeneral formula I:

a) i) thiourea, NaOMe, MeOH, rt; ii) Mel, DMSO, rt; iii) POCl₃,dimethylaniline, 100-120° C.; b) R¹—SO₂—NHK, DMSO, rt; c) 18, KOtBu,THF, rflx; d) MCPBA, DCM, rt; ii) for the substitution of the sulfonogroup see [5]; e) HO—(CH₂)n—NH₂, NaH, THF/DMF, 0° C. to rt; f)R²—SO₂—Cl, base, DCM, rt; g) MCPBA, DCM, rt; h) for the substitution ofthe sulfono group see [5].

EXAMPLES

The following examples illustrate the invention but do not at all limitthe scope thereof. All temperatures are stated in ° C.

The following compounds were prepared according to the proceduredescribed above and shown in Scheme 1. All compounds were characterizedby 1H-NMR (300 MHz) and occasionally by 13C-NMR (75 MHz) (Varian Oxford,300 MHz; chemical shifts are given in ppm relative to the solvent used;multiplicities: s=singlet, d=doublet, t=triplet; m=multiplet), by LC-MS(Waters Micromass; ZMD-platform with ESI-probe with Alliance 2790 HT;Colum: 2×30 mm, Gromsil ODS4, 3 μm, 120A; Gradient: 0-100% acetonitrilin water, 6 min, with 0.05% formic acid, flow: 0.45 ml/min; t_(R) isgiven in min.), by TLC (TLC-plates from Merck, Silica gel 60 F₂₅₄) andoccasionally by melting point.

Example 1

a) 318 mg N-(2-Hydroxy-ethyl)-methanesulfonamide was dissolved in 15 mlTHF and 673 mg potassium-tert.-butylate was added. The mixture washeated to reflux for 15 min, then cooled to room temperature and 200 mgofp-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene-sulfonamidefollowed by 1 ml of DMSO was added and the reaction mixture was heatedto reflux for another 8 h. The THF was evaporated and 50 ml of water wasadded to the residue which was acidified to pH 4 by addition of aceticacid. The product precipitates, was filtered off and recrystallized frommethanol/diethylether. 150 mg ofp-methyl-N-[6-(ethoxy-2-methanesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzenesulfonamidewas obtained as a yellow solid. R_(f) (EA/cyHex=3/1)=0.311; t_(R)=4.94(LC); M⁺=586.55 (ES+); M⁺=584.45 (ES−)

b) To a solution of 0.23 g sodium in 40 ml methanol was added 10.62 g4-cyanopyridine at room temperature. Stirring was continued for 6 hfollowed by the addition of 5.9 g ammoniumchloride and stirring wascontinued for another 10 h. Then 120 ml diethylether was added and theprecipitate was filtered off after 30 min and washed once with 20 ml ofdiethylether. The product was dried under highly reduced pressure. 14.95g 4-amidino-pyridine hydrochloride was obtained as a white powder.

c) 48 ml 2-methoxy-phenol (guajacol) was slowly added to a stirredsuspension of 70.8 g potassium carbonate in 480 ml acetone followed byheating to 45° C. Then 63.2 ml dimethylchloromalonate in 50 ml acetonewas added within 20 min. The reaction mixture was heated to reflux for16 h. The solvent was evaporated under reduced pressure, the residuetaken into water and extracted with dichloromethane. The combinedorganic layers were dried over sodium sulfate and evaporated. The oilyproduct was crystallized from methyl-tert.-butyl-ether. 86 gdimethyl-(o-methoxyphenoxy)malonate was obtained.

d) To a stirred solution of 9.7 g sodium methylate in 100 ml methanol asolution of 21.7 g dimethyl-(o-methoxyphenoxy)malonate in 50 ml methanolwas added within 15 min and stirring was continued for 30 min followedby the addition of 15.0 g 4-amidino-pyridine hydrochloride followed bystirring at room temperature for 20 h. The reaction mixture wasconcentrated in vacuo. The solid residue was stirred with ether. Theobtained powder was filtered off and dissolved in 300 ml water. Aceticacid was added to pH=4. The precipitated product was filtered off,washed with water and dried in vacuo at 50° C. 20.1 g5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-pyrimidine (is possiblyalso present as the tautomeric5-(o-methoxyphenoxy)-2-(4-pyridyl)-tetrahydropyrimidine-4,6-dion) wasobtained as a white powder.

e) 10 g of the5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-pyrimidine, 11.2 gN-ethyldiisopropylamine, 11 g tetraethylammoniumchloride and 13.8 gphosphorous pentachloride was dissolved in 25 ml phosphorous oxychlorideand heated to reflux for 3 h. The mixture was evaporated in vacuo,toluene was added and the mixture was again evaporated. The residue wastaken into dichloromethane and poured onto ice/water. The layers wereseparated, the organic layer was washed with water, dried over sodiumsulfate and evaporated. After recrystallization from acetone, 6.52 g of5-(o-methoxyphenoxy)-4,6-dichloro-2-(4-pyridyl)-pyrimidine was obtained.

f) 25 g toluene-4-sulfonylchloride was dissolved in 300 ml THF andcooled to 0° C. followed by the addition of 31 ml of 25% aqueousammonia. After stirring the reaction mixture at room temperature for onehour, the solvent was evaporated and the residue taken into ethylacetate, washed twice with water, dried over sodium sulfate andevaporated. The white solid obtained was dissolved in 150 ml methanol,15 g potassium-tert.-butylate was added and stirring continued for 30min. The reaction mixture was evaporated and dried under highly reducedpressure. 24.9 g p-toluene-sulfonamide potassium salt was obtained as awhite powder.

g) 2 g 5-(o-methoxyphenoxy)-4,6-dichloro-2-(4-pyridyl)-pyrimidine wasdissolved in 30 ml dry DMSO. 2.40 g p-toluene-sulfonamide potassium saltwas added and stirring continued for 20 h. The reaction mixture waspoured onto 200 ml water and extracted twice with 200 ml diethylether.The combined organic layers were extracted twice with 50 ml water. Thecombined water layers were acidified by acetic acid to pH=4. Theprecipitated product was filtered off, washed with ether and dried underreduced pressure. 1.9 gp-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamidewas obtained as a slightly colored solid. R_(f) (EA/Hex=1/1)=0.15.

Example 2

According to Example 1a), 200 mgp-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamide(Example 1g) was reacted with 459 mgN-(2-hydroxy-ethyl)-benzenesulfonamide to give 150 mgp-methyl-N-[6-(ethoxy-2-benzenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamide.R_(f) (EA/cyHex=3/1)=0.574; t_(R)=5.66 (LC); M⁺=646.52 (ES−).

Example 3

According to Example 1a), 200 mgp-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamide(Example 1g) was reacted with 490 mgN-(2-hydroxy-ethyl)-p-toluenesulfonamide to give 130 mgp-methyl-N-[6-(ethoxy-2-p-toluenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamide.R_(f) (EA/cyHex=3/1)=0.529; t_(R)=5.83 (LC); M⁺=662.69 (ES+); M⁺=660.56(ES−).

Example 4

a) 150 mgp-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas dissolved in 5 ml dry dichloromethane and 1 ml dry DMF. 150 mgHünig's base and 100 mg mesylchloride was added and stirring wascontinued for 12 h. The solvent was evaporated and 20 ml of water wasadded to the residue. The product precipitated and was filtered off andwashed with water. After recrystallization from methanol/diethylether100 mg ofp-tert.-butyl-N-[6-(ethoxy-2-methanesulfonamido)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamideas a reddish solid was obtained. t_(R)=5.39 (LC); M⁺=627.84 (ES−).

b) 1.75 g sodium hydride (55% in mineral oil) was washed twice with dryTHF. 8 ml of THF was then added and the mixture was cooled to 0° C.followed by slow addition of 8 ml of abs. ethanolamine in 8 ml of dryTHF. The mixture was stirred for 1 hour at room temperature and was thenslowly added to a solution of 1 gp-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidein 11.5 ml dry DMF at 0° C. Stirring was continued at room temperaturefor 12 h. The reaction mixture was poured onto water and acidified with25% hydrochloric acid to pH=7. A white solid precipitates; it wasfiltered off, washed with water and dried at 45° C. under reducedpressure. 690 mgp-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas obtained as a yellow powder. R_(f) (EA/cyHex=3/1)=0.389.

c)p-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas prepared as disclosed in EP 0 526 708 A1 from4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine.

d) 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine wasprepared as disclosed in EP 0 526 708 A1 from4,6dihydroxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (whichmay also be present in the tautomeric form as5-(o-methoxyphenoxy)-2-(2-pyrimidinyl) -tetrahydropyrimidine4,6-dion).

e) 4,6-dihydroxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine [orits tautomer5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-tetrahydropyrimidine-4,6-dion]was prepared as disclosed in EP 0 526 708 A1 from 2-amidinopyrimidineand dimethyl-(o-methoxyphenoxy)malonate.

Example 5

According to Example 4a), 150 mgp-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas reacted with 146 mg trifluoromethanesulfonylchloride to give 100 mgofp-tert.-butyl-N-[6-(ethoxy-2-trifluoromethanesulfonamido)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamideas a yellow solid. t_(R)=5.97 (LC); M⁺=683.76 (ES+); M⁺=681.83 (ES−)

Example 6

According to Example 1a), 263 mgp-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas reacted with 592 mg N-(2-hydroxy-ethyl)-p-toluenesulfonamide and 673mg potassium tert.-butylate in THF to give 30 mg ofp-tert.-butyl-N-[6-(ethoxy-2-p-toluenesulfonamido)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamideas a white solid. t_(R)=5.67 (LC); M⁺=705.71 (ES+); M⁺=703.81 (ES−)

Example 7

According to Example 1a), 526 mgp-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas reacted with 1.1 g N-(2-hydroxy-ethyl)-2-thiophenesulfonamide and660 mg potassium tert.-butylate in THF to give 210 mg ofp-tert.-butyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamideas a white solid. t_(R)=5.50 (LC); M⁺=697.64 (ES+); M⁺=695.69 (ES−)

Example 8

According to Example 4a), 90 mgp-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas reacted with 63 mg ethanesulfonylchloride to give 60 mg ofp-tert.-butyl-N-[6-(ethoxy-2-ethanesulfonamido)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamideas a slightly yellow solid. t_(R)=5.14 (LC); M⁺=641.85 (ES−)

Example 9

According to Example 4a), 70 mgp-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas reacted with 80 mg p-methoxybenzenesulfonylchloride to give 50 mg ofp-tert.-butyl-N-[6-(ethoxy-2-p-methoxybenzenesulfonamido)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamideas a white solid. t_(R)=5.57 (LC); M⁺=719.89 (ES−)

Example 10

a) According to Example 1a), 256 mg5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 460 mg N-(2-Hydroxy-ethyl)-2-propanesulfonamide and 673mg potassium tert.-butylate in THF to give 140 mg of5-i.-propyl-N-[6-(ethoxy-2-(2-propanesulfonamido))-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. 1H-NMR (d6-DMSO): 8.61(d, 2H); 8.59(s, 1H); 8.20(d,1H); 8.04(d, 1H); 7.75(d, 2H); 7.0(m, 2H); 6.79(m, 2H); 4.39(t, 2H);3.90(s, 3H); 3.16(m, 2H); 3.03(m, 2H); 1.10(d, 6H); 1.04(d, 6H).

b)5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyrdyl)-4-pyrimidin-yl]pyridine-2-sulfonamideand its precursors are prepared according to procedures disclosed in WO96/19459.

Example 11

According to Example 1a), 300 mg5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 592 mg N-(2-Hydroxy-ethyl)-4-methylbenzenesulfonamideand 673 mg potassium tert.-butylate in THF to give 310 mg of5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.33 (LC); M⁺=780.80 (ES+).

Example 12

According to Example 1a), 256 mg5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 592 mg N-(2-hydroxy-ethyl)-4-methylbenzenesulfonamideand 673 mg potassium tert.-butylate in THF to give 220 mg of5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=4.96 (LC); M⁺=689.77 (ES−); M⁺=691.68 (ES+).

Example 13

According to Example 1a), 256 mg5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 553 mg N-(2-hydroxy-ethyl)benzenesulfonamide and 673 mgpotassium tert.-butylate in THF to give 260 mg of5-i.-propyl-N-[6-(ethoxy-2-benzenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=4.76 (LC); M⁺=677.64 (ES+); M⁺=675.80 (ES−).

Example 14

According to Example 1a), 256 mg5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 383 mg N-(2-hydroxy-ethyl)-methanesulfonamide and 673mg potassium tert.-butylate in THF to give 110 mg of5-i.-propyl-N-[6-(ethoxy-2-methanesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=4.13 (LC); M⁺=613.73 (ES−); M⁺=615.60 (ES+).

Example 15

a) According to Example 4a), 300 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 132 mg 2-thiophenesulfonylchloride to give 56 mg5-i.-propyl-N-[6-(ethoxy-2-thiophenesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.55 (LC); M⁺=772.74 (ES+); M⁺=770.86 (ES−).

b)5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamideis prepared according to Example 4b).

c)5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamideis prepared according to procedures disclosed in WO 96/19459 and EP 0526 708 A1.

Example 16

According to Example 4a), 150 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 0.08 ml 1-propanesulfonylchloride to give 56 mg5-i.-propyl-N-[6-(ethoxy-2-(1-propanesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.39 (LC); M⁺=732.74 (ES+); M⁺=730.82 (ES−).

The precursors are prepared according to Example 15b) and c).

Example 17

According to Example 4a), 100 mgp-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamidewas reacted with 1-butanesulfonylchloride to givep-tert.-butyl-N-[6-(ethoxy-2-(1-butanesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamideas a slightly yellow solid. t_(R)=5.51 (LC); M⁺=671.81 (ES+); M⁺=669.90(ES−).

The precursors are prepared according to example 15b) and c).

Example 18

According to Example 4a), 150 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 2-propanesulfonylchloride to give 60 mg5-i.-propyl-N-[6-(ethoxy-2-(2-propanesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.41 (LC); M⁺=732.84 (ES+); M⁺=730.92 (ES−).

The precursors are prepared according to Example 15b) and c).

Example 19

According to Example 4a), 150 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 2-thiophenesulfonylchloride to give 65 mg5-i.-propyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.57 (LC); M⁺=743.68 (ES+); M⁺=741.75 (ES−).

The precursors are prepared according to Example 15b) and c).

Example 20

According to Example 4a), 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methly-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with ethanesulfonylchloride to give 40 mg5-i.-propyl-N-[6-(ethoxy-2-ethanesulfonamido)-5-(o-methoxyphenoxy)-2-methyl-4-pyrmidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.28 (LC); M⁺=658.63 (ES+); M⁺=656.70 (ES−).

The precursors are prepared according to Example 15b) and c).

Example 21

According to Example 4a), 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methly-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with p-toluenesulfonylchloride to give 60 mg5-i.-propyl-N-[6-(ethoxy-2-p-toluenesulfonamido)-5-(o-methoxyphenoxy)-2-methyl-4-pyrmidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.26 (LC); M⁺=628.73 (ES+); M⁺=626.74 (ES−).

The precursors are prepared according to Example 15b) and c).

Example 22

According to Example 4a), 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 2-thiophenesulfonylchloride to give 55 mg5-i.-propyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=5.06 (LC); M⁺=620.57 (ES+); M⁺=618.64 (ES−).

The precursors are prepared according to Example 15b) and c).

Example 23

According to Example 4a), 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methly-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with methanesulfonylchloride to give 45 mg5-i.-propyl-N-[6-(ethoxy-2-methanesulfonamido)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]pyridine-2-sulfonamideas a white solid. t_(R)=4.47 (LC); M⁺=552.56 (ES+); M⁺=550.66 (ES−).

Example 24

a) At 0° C. a solution of 14.2 g of diethyl 2-(p-tolyl)-malonate in 50ml of methanol was slowly added to a solution of 9.4 g of sodiummethylate in 300 ml of methanol. Upon completion of the addition thereaction mixture was allowed to warm up and 5.4 g of formamidinehydrochloride was added. The mixture was stirred at room temperature for16 h. The solvent was removed under reduced pressure and the remainingresidue was treated with 150 ml of 2 N hydrochloric acid. The suspensionwas stirred for 0.5 h. At 0-5° C., the pH was carefully adjusted to 4using 10 N sodium hydroxide solution. The precipitate was collected,washed with cold water, isopropanol, and diethyl ether and dried underhigh vacuum at 65° C. to give 11.2 g of4,6-dihydroxy-5-(p-tolyl)-pyrimidine (or a tautomer) as a white powder.

b) At room temperature 10 ml of N,N-dimethylaniline was added to amixture of 5.1 g of 4,6-dihydroxy-5-(p-tolyl)-pyrimidine and 75 ml ofPOCl₃. The reaction mixture was stirred at 70° C. for 16 h. The excessof POCl₃ was distilled off and the remaining oil was treated with anice/water mixture and extracted three times with diethyl ether. Thecombined organic layers was washed with 1N aqueous hydrochloric acidfollowed by brine, dried over MgSO₄ and evaporated. The remaining brownoil was crystallised from isopropanol. The pale yellow crystals wascollected, washed with cold isopropanol and dried under high vacuum tofurnish 4.1 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine.

c) A mixture of 0.8 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine and 1.68 gof 4-tert.-butylbenzene sulfonamide potassium salt in 20 ml of DMSO wasstirred at room temperature for 24 h. The mixture was poured onto 200 mlof water and extracted twice with 100 ml of diethyl ether. The organiclayers was extracted twice with 50 ml of water. The combined aqueouslayers was acidified with conc. hydrochloric acid. The resulting finesuspension was extracted twice with ethyl acetate. The combined organiclayers was dried over Na₂SO₄ and evaporated. The residue was dried underhigh vacuum to give 1.34 g4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamideas a white powder. LC-MS: t_(R)=5.92 min, [M+1]⁺=416.20, [M−1]⁻=414.24.

d) 100 mg 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzenesulfonamide was dissolved in 5 ml dry THF. 162 mg ofpotassium-tert.-butylate and 200 mg ofN-(2-hydroxyethyl)-N-methyl-ethanesulfonamide was added and the mixturewas heated to reflux for 8 h then cooled to room temperature. Ethylacetate was added and the precipitated side product was filtered off.The filtrate was concentrated in vacuo. The crude product was purifiedby column chromatography (silica gel; ethyl acetate) to give 45 mg of4-tert.-butyl-N-{6-[2-(ethanesulfonyl-methyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.58 min, [M−1]⁻=545.54.

Example 25

According to Example 24d) 100 mg4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamidewas reacted with N-(2-hydroxyethyl)-N-methyl-toluenesulfonamide to give14 mg4-tert.-butyl-N-{6-[2-(toluene-sulfonyl-methyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=6.18 min, [M−1]⁻=607.54.

Example 26

a) According to Example 4b), 500 mg4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamidewas reacted with 2-amino-ethanol to give 450 mgN-[6-(2-amino-ethoxy)-5-p-tolyl-pyrimidin-4-yl]4-tert.-butyl-benzenesulfonamide.LC-MS: t_(R)=3.90 min, [M−1]⁻=439.44.

b) According to Example 4a) with DBU instead of Hünig's base, 200 mgN-[6-(2-amino-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-4-tert.-butyl-benzenesulfonamidewas reacted with tosylchloride to give 147 mg4-tert.-butyl-N-{6-[2-(toluenesulfonyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.85 min, [M−1]⁻=593.50.

Example 27

a) At 5° C. 12.7 g of sodium methylate was added portionwise to asolution of 18.9 g of dimethyl-2-(o-methoxyphenoxy)malonate in 450 ml ofmethanol. Upon completion of the addition stirring was continued at roomtemperature for 30 min followed by the addition of 6 g of formamidinehydrochloride. The mixture was stirred at room temperature for 72 h.Eventually, the solvent was removed under reduced pressure and theremaining residue was suspended in diethyl ether. The solid material wasfiltered off and dissolved in 100 ml of water. The solution wasacidified with conc. hydrochloric acid. A white precipitate formed. Theprecipitate was collected, washed with water and dried to give 15.1 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-pyrimidine (or a tautomer) as a whitepowder.

b) To a solution of 7.5 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-pyrimidine in 90 ml of POCl₃ 24 ml ofN,N-dimethylaniline was added. The mixture was heated to 160° C. andstirred for 2.5 h. Excess of POCl₃ was distilled off under reducedpressure. Traces of POCl₃ was coevaporated with toluene. The remainingoil was treated with a water:ice mixture. The mixture was acidified with1 N hydrochloric acid and extracted twice with diethyl ether. Thecombinded organic layers was washed twice with dilute aqueoushydrochloric acid, dried over MgSO₄ and evaporated. The remaining solidwas washed with methanol and dried. This gave 4.75 g of4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine as a pale yellow powder.

c) To a solution of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidinein 40 ml of DMSO 3.7 g of 4-tert.-butylbenzene sulfonamide potassiumsalt was added. The resulting solution was stirred for 20 h at roomtemperature. Eventually, the mixture was poured onto 400 ml of water andwashed twice with 200 ml of diethyl ether. The organic layers wasextracted with 200 ml of water. The combinded aqueous layers wasacidified with conc. hydrochloric acid. The mixture was cooled to 0° C.and 100 ml of brine was added. The precipitate that formed was collectedand dried to yield 2.7 g of4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-benzenesulfonamide as a white powder. LC-MS: t_(R)=5.80 min, [M+1]⁺=448.17,[M−1]⁻=446.21.

d) According to Example 4b) 1.13 g4-tert.-butyl-N-[6-chloro-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide was reacted with 2-amino-ethanol to give 1.08 g4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide. LC-MS: t_(R)=3.81 min, [M−1]⁻=471.41

e) According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide was reacted with 166 mg 4-bromobenzenesulfonylchloride togive 106 mg4-tert.-butyl-N-{6-[2-(4-bromobenzenesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.95 min, [M−1]⁻=691.41.

Example 28

According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide was reacted with 123 mg 4-methylbenzenesulfonylchloride togive 125 mg4-tert.-butyl-N-{6-[2-(4-methylbenzenesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pydmidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.80 min, [M−1]⁻=625.52.

Example 29

According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide was reacted with 121 mg thiophen-2-sulfonylchloride to give73 mg4-tert.-butyl-N-{6-[2-(2-thiophenesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pydmidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.61 min, [M−1]⁻=617.42.

Example 30

According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide was reacted with 93 mg 1-propanesulfonylchloride to give 110mg4-tert.-butyl-N-{6-[2-(1-propanesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.43 min, [M−1]⁻=577.49.

Example 31

According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide was reacted with 84 mg ethanesulfonylchloride to give 98 mg4-tert.-butyl-N-{6-[2-(ethanesulfonylamino)-ethoxy]-5-(o-methoxy-phenoxy)-pydmidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.25 min, [M−1]⁻=563.46.

Example 32

According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide was reacted with 74 mg methanesulfonylchloride to give 24 mg4-tert.-butyl-N-{6-[2-(methanesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide.LC-MS: t_(R)=5.11 min, [M−1]⁻=549.45.

Example 33

a) 2.77 g 4,6-dichloro-2-methylthio-5-phenylpyrimidine was dissolved in50 ml DMSO and 3.42 g 4-tert-butylbenzenesulfonamide potassium salt and1 ml Hünig's base was added. Stirring was continued for 24 h. Themixture was poured onto 400 ml water, washed with diethylether andacidified with conc. hydrochloric acid. The product precipitated and wasfiltered off and dried in vacuo to give 4 g of4-tert.-butyl-N-(6-chloro-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl)-benzenesulfonamide.LC-MS: t_(R)=6.29 min, [M+1]⁺=448.17; 459.17.

b) 4.0 g4-tert.-butyl-N-(6-chloro-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl)-benzenesulfonamide was reacted with 2-aminoethanol according to Example4b) to give 1.65 g4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=3.75 min, [M−1]⁻=471.38.

c) According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamidewas reacted with 123 mg toluene-4-sulfonylchloride to give 120 mg4-tert.-butyl-N-[6-(2-(p-methylphenylsulfonyl)-amino)-ethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=6.16 min. [M−1]⁻=625.49.

Example 34

According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamidewas reacted with 121 mg thiophene-2-sulfonylchloride to give 115 mg4-tert.-butyl-N-[6-(2-(2-thiophenesulfonyl)-amino)-ethoxy)-2-methylsulfanyl-5-phenyl-pydmidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=5.98 min, [M−1]⁻=617.39.

Example 35

According to Example 4a) 100 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamidewas reacted with 83 mg ethanesulfonylchloride to give 56 mg4-tert.-butyl-N-[6-(2-(ethanesulfonyl)-amino)-ethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=5.68 min. [M−1]⁻=563.42.

Example 36

a) 12.15 g sodium methylate was dissolved in 200 ml methanol and 21.1 gdimethyl-(o-methoxyphenoxy)malonate was added. Stirring was continuedfor 130 min. The mixture was cooled to 10° C. and 7.6 g thiourea wasadded. Stirring was continued for 24 h. The solvent was evaporated invacuo. The residue was stirred with diethyl ether. The ether layer wasfiltered off and the solid was dissolved in 60 ml water and acidified topH=4 with conc. acetic acid. The precipitated product was filtered andwashed with methanol and dried at 30° C. and reduced pressure to give19.8 g 5-(o-methoxyphenoxy)-2-thioxo-dihydro-pyrimidine-4,6-dione (or atautomere thereof.

b) 19.8 g 5-(o-methoxyphenoxy)-2-thioxo-dihydro-pyrimidine-4,6-dione wasdissolved in 100 ml DMSO and 10.28 g potassium carbonate was added.After 30 min 4.36 ml methyl iodide was added in portions within 10 min.Stirring was continued for 4 h followed by the addition of 250 ml water.The solution was acidified with 25% hydrochloric acid. The precipitatedproduct was filtered off, washed with diethylether and dried in vacuo togive 12.9 g 5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidine-4,6-diol.LC-MS: t_(R)=3.01 min, [M−1]⁻=279.15.

c) 10 g 5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidine-4,6-diol wasdissolved in 50 ml phosphorous oxychloride and 16.7 mlN,N-dimethylaniline and heated to reflux for 3.5 h. Then toluene wasadded and the reaction mixture was evaporated. Then ice/water was slowlyadded followed by the addition of conc. hydrochloric acid. This mixturewas extracted with ethylacetate and diethylether followed by filtrationthrough activated charcoal and evaporation of the solvent. The residuewas crystallized from diethylether/n-hexane to give 6.34 g5-(o-methoxyphenoxy)-2-methylsulfanyl-4,6-dichloro-pyrimidine.

d) 5 g 5-(o-methoxyphenoxy)-2-methylsulfanyl-4,6-dichloro-pyrimidine wasdissolved in 50 ml DMSO and 8.8 g tert.-butylphenylsulfonamide potassiumsalt was added and stirring was continued for 24 h. The mixture waspoured onto 400 ml water and acidified with conc. hydrochloric acid. Theprecipitated product was filtered off and washed with an additionalportion of water. After drying at reduced pressure 4.64 g4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamidewas obtained. LC-MS: t_(R)=6.22 min, [M−1]⁻=492.26.

e) According to the procedure described in Example 4b) 4.2 g4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamidewas transformed to 4.4 g4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=4.14 min, [M−1]⁻=517.34.

f) According to the procedure described in Example 4a) 2 g of4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamidewas reacted with 0.81 g ethanesulfonylchloride to give 0.7 g4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=5.85 min, [M+1]⁺=611.31.

g) 305 mg4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamidewas dissolved in 2 ml dichloromethane at 0° C. followed by the additionof 271 mg m-chloroperbenzoic acid dissolved in 3 ml dichloromethane.Stirring was continued for 1 hour at 0° C. and 2 h at room temperature.Then sodium bisulfite solution was added and the organic layer wasseparated and washed with water, dried, concentrated and chromatographedover silicagel with ethyl acetate/n-hexane to give 250 mg4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-methanesulfonyl-5-(o-methoxyphenoxy-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=5.17 min, [M+1]⁺=643.32.

Example 37

According to Example 36f) 2 g of4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamidewas reacted with 1.19 g p-toluenesulfonylchloride to give 0.9 g4-tert.-butyl-N-[6-(2-p-toluenesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=6.24 min, [M+1]⁺=673.34.

Example 38

a) According to the procedure described in Example 1g) 3.3 g4,6-dichloro-2-cyclopropyl-5-(o-methoxyphenoxy)-pyrimidine (preparedaccording to procedures described in Example 1) was reacted with5-i-propyl-2-pyridyl-sulfonamide potassium salt to give 4.04 g5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.64 min, [M−1]⁻=473.29.

b) According to the procedure described in Example 4b)5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamidewas reacted with 2-aminoethanol to give 950 mg5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide.LC-MS: t_(R)=3.66 min, [M−1]⁻=498.37.

c) According to the procedure described in Example 4a), 250 mg5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamidewas reacted with 4-methylbenzenesulfonylchloride to give 100 mg5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.32 min, [M−1]⁻=604.39.

Example 39

According to the procedure described in Example 4a), 250 mg5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamidewas reacted with 4-methylbenzenesulfonylchloride to give 140 mg5-i-propyl-N-[6-(2-(4-methylbenzene)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.69 min. [M−1]⁻=652.39.

Example 40

a) According to the procedure described in Example 1g) 3.3 g4,6-dichloro-2-cyclopropyl-5-(o-methoxyphenoxy)-pyrimidine (preparedaccording to procedures described in Example 1) was reacted with4-tert.-butylphenylsulfonamide potassium salt to give 4.22 g4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide.LC-MS: t_(R)=6.24 min, [M+1]⁺=488.23.

b) According to the procedure described in Example 4b)4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamidewas reacted with 2-aminoethanol to give 1.28 g4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide.LC-MS: t_(R)=4.04 min, [M−1]⁻=511.50.

c) According to the procedure described in Example 4a), 256 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamidewas reacted with 2-propanesulfonylchloride to give 150 mg4-tert.-butyl-N-[6-(2-(2-propane)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide.LC-MS: t_(R)=5.88 min, [M−1]⁻=617.36.

Example 41

According to the procedure described in Example 4a), 256 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamidewas reacted with 4-methylbenzene-sulfonylchloride to give 160 mg4-tert.-butyl-N-[6-(4-methylbenzene)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide.LC-MS: t_(R)=6.25 min, [M−1]⁻=665.37.

Example 42

a) A solution of 32.75 g of dimethyl-(o-methoxyphenoxy)malonate in 250ml of methanol was cooled to 0° C. 20.0 g sodium methylate was addedportionwise and upon completion of the addition the mixture was stirredat room temperature for 6 h. Then 25.0 g of morpholinoformamidinehydrobromide was added and stirring was continued for 72 h. The solventof the beige suspension was evaporated and the residue was washed twicewith 150 ml of diethyl ether. The remaining powder was dissolved in 200ml of water. Upon adjusting the pH to 4 with 50 ml of acetic acid aprecipitate formed. The precipitate was collected, washed with water anddried under high vacuum to yield 17.01 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino)-pyrimidine (or atautomer) as a slightly beige powder.

b) At 0° C. 50 ml of POCl₃ was carefully added to 27.5 ml of Hünig'sbase. To this mixture 17 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino)-pyrimidine was addedportionwise. The resulting mixture was stirred over night at 130° C. Theexcess of reagents was evaporated and traces of POCl₃ was removed bycoevaporation with toluene. The black residue was treated with 50 ml ofDCM and 50 ml of a water/ice mixture. After stirring for 15 min, themixture was diluted with 400 ml of water and 400 ml of DCM. The organiclayer was separated and washed with 300 ml of water. The aqueous layerwas extracted with 400 ml of DCM. The combined DCM layers was dried overNa₂SO₄ and the solvent was removed to a volume of about 100 ml. Theremaining solution was filtered over 50 g of silica gel eluting withDCM. The filtrate was evaporated. The resulting residue was suspended in50 ml of diethyl ether. The solid was filtered off and dried to give13.85 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-pyrimidineas a white crystalline powder.

c) To a suspension of 4 g of4,6-dichloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-pyrimidine in 60 mlof DMSO was added 5.32 g of 5-isopropyl-2-pyridine sulfonamide potassiumsalt and 0.98 ml of Hünig's base. The mixture was stirred at 65° C. for72 h. The dark solution was poured onto 500 ml of water and quicklyfiltered through celite. The filtrate was extracted with 500 ml and 250ml of diethyl ether. The organic layers were extracted with 100 ml ofwater. The aqueous layers were combined, acidified with 3.5 ml of aceticacid and cooled to 0° C. The precipitate that formed was collected,washed with cold water and dried under high vacuum to furnish 4.94 g of5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide as a brownish powder. LC-MS: t_(R)=5.46 min, [M+1]⁺=520.22,[M−1]⁻=518.36.

d) According to the procedure described in Example 4b) 2 g5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 2-aminoethanol to give 750 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=3.45 min, [M+1]⁺=545.58, [M−1]⁻=543.68.

e) According to the procedure described in Example 4a) 70 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with thiophen-2-sulfonylchloride to give 42 mg5-isopropyl-N-[6-(2-(2-thiophensulfonyl)-amino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=5.28 min, [M+1]⁺=691.28.

Example 43

According to Example 39) 250 mg5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamidewas reacted with ethanesulfonylchloride to give 212 mg5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.18 min, [M−1]⁻=589.93.

Example 44

According to Example 40) 256 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamidewas reacted with ethanesulfonylchloride to give 120 mg4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide.LC-MS: t_(R)=5.79 min. [M−1]⁻=603.90.

Example 45

According to the procedure described in Example 4a) 70 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with methanesulfonylchloride to give 50 mg5-isopropyl-N-[6-(2-methanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.80 min, [M+1]⁺=623.37.

Example 46

According to the procedure described in Example 4a) 70 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 1-propanesulfonylchloride to give 56 mg5-isopropyl-N-[6-(2-(1-propane)sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=5.11 min, [M+1]⁺=651.32.

Example 47

a) According to the procedure described in Example 4b) 1.04 g5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 3-aminopropanol to give 850 mg5i.-propyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=3.25 min, [M+1]⁺=551.33.

b) According to the procedure described in Example 4a) 200 mg5-i.-propyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-pyridine-2-sulfonamidewas reacted with methanesulfonylchloride to give 130 mg5-i.-propyl-N-[6-(3-methanesulfonylamino-propoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-pyridine-2-sulfonamide.LC-MS: t_(R)=4.22 min, [M+1]⁺=629.25.

Example 48

According to the procedure described in Example 4a) 200 mg5-i.-propyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-pyridine-2-sulfonamidewas reacted with 1-propanesulfonylchloride to give 120 mg5-i.-propyl-N-[6-(3-(1-propane)sulfonylamino-propoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-pyridine-2-sulfonamide.LC-MS: t_(R)=4.55 min, [M+1]⁺=657.35.

Example 49

a) To a stirred solution of 22.9 g sodium methylate in 250 ml methanolwas added 37.5 g dimethyl-2-(o-methoxyphenoxy)malonate in portionswithin 15 min. Stirring was continued for 30 min. Then 15.8 gtrifluoro-acetamidine was added followed by stirring for 20 h at roomtemperature. Work up was done according to the procedure described inExample 1d) to give 29.77 g5-(o-methoxyphenoxy)-2-trifluoromethyl-pyrimidine-4,6-dione (or itstautomeric form). LC-MS: t_(R)=3.41 min, [M+1]⁺=303.32.

b) According to the procedure described in Example 1e) 29.77 g5-(o-methoxyphenoxy)-2-trifluoromethyl-pyrimidine-4,6-dione (or itstautomeric form) was transformed to 23.95 g5-(o-methoxyphenoxy)-4,6-dichloro-2-trifluoromethyl-pyrimidine. LC-MS:t_(R)=5.48 min.

c) According to the procedure described in Example 1g) 4.0 g5-(o-methoxyphenoxy)-4,6-dichloro-2-trifluoromethyl-pyrimidine wasreacted with 5-i-propyl-pyridine-2-sulfonamide potassium salt in DMSO togive 4.03 g5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-trifluoromethyl4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=5.24 min, [M+1]⁺=503.44.

d) According to the procedure described in Example 4b) 2.0 g5-i.-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 2-aminoethanol to give 1.14 g5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=4.87 min, [M+1]⁺=528.41.

e) According to the procedure described in Example 4a) 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 1-butanesulfonylchloride to give 110 mg5-i.-propyl-N-[6-(2-butanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=5.41 min, [M+1]⁺=648.49.

Example 50

According to the procedure described in Example 4a) 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 1-propanesulfonylchloride to give 110 mg5-i.-propyl-N-[6-(2-(1-propane)sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=5.21 min, [M+1]⁺=634.47.

Example 51

According to the procedure described in Example 4a) 20 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene-sulfonamidewas reacted with thiophene-2-sulfonylchloride to give 20 mg4-tert.-butyl-N-[6-(2-(thiophene-2-sulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene-sulfonamide.LC-MS: t_(R)=5.17 min, [M+1]⁺=696.57.

Example 52

a) A solution of 32.75 g of dimethyl-(o-methoxyphenoxy)malonate in 250ml of methanol was cooled to 0° C. 20.0 g sodium methylate was addedportionwise and upon completion of the addition the mixture was stirredat room temperature for 6 h. Then 25.0 g of morpholinoformamidinehydrobromide was added and stirring was continued for 72 h. The solventof the beige suspension was evaporated and the residue was washed twicewith 150 ml of diethyl ether. The remaining powder was dissolved in 200ml of water. Upon adjusting the pH to 4 with 50 ml of acetic acid aprecipitate formed. The precipitate was collected, washed with water,and dried under high vacuum to yield 17.01 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino)-pyrimidine (or atautomer) as a slightly beige powder.

b) At 0° C. 50 ml of POCl₃ was carefully added to 27.5 ml of Hünig'sbase. To this mixture 17 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino)-pyrimidine was addedportionwise. The resulting mixture was stirred over night at 130° C. Theexcess of reagents was evaporated and traces of POCl₃ was removed bycoevaporation with toluene. The black residue was treated with 50 ml ofDCM and 50 ml of a water/ice mixture. After stirring for 15 min, themixture was diluted with 400 ml of water and 400 ml of DCM. The organiclayer was separated and washed with 300 ml of water. The aqueous layerwas extracted with 400 ml of DCM. The combined DCM layers were driedover Na₂SO₄ and the solvent was removed to a volume of about 100 ml. Theremaining solution was filtered through 50 g of silica gel eluting withDCM. The filtrate was evaporated. The resulting residue was suspended in50 ml of diethyl ether. The solid was filtered off and dried to give13.85 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-pyrimidineas a white crystalline powder.

c) To a suspension of 4 g of4,6-dichloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-pyrimidine in 60 mlof DMSO was added 5.32 g of 5-isopropyl-2-pyridine sulfonamide potassiumsalt (Example 3c) and 0.98 ml of Hünig's base. The mixture was stirredat 65° C. for 72 h. The dark solution was poured onto 500 ml of waterand quickly filtered through celite. The filtrate was extracted with 500ml and 250 ml of diethyl ether. The organic layers were extracted with100 ml of water. The aqueous layers were combined, acidified with 3.5 mlof acetic acid and cooled to 0° C. The precipitate that formed wascollected, washed with cold water and dried under high vacuum to furnish4.94 g of5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide as a brownish powder. LC-MS: t_(R)=5.46 min, [M+1]⁺=520.22,[M−1]⁻=518.36.

d) According to the procedure described in Example 1a) 260 mg5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 630 mgN-(3-hydroxy-propyl)4-methylbenzenesulfonamide in THF in the presence ofpotassium tert.-butylate to give 270 mg5-isopropyl-N-[6-(3-((4-methylbenzene)-sulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=5.27 min, [M+1]⁺=713.67, [M−1]⁻=711.71.

Example 53

According to the procedure described in Example 4a) 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 4-methylbenzene-sulfonylchloride to give 120 mg5-i.-propyl-N-[6-(2-((4-methylbenzene)-sulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=5.61 min, [M+1]⁺=682.51, [M−1]⁻=680.50.

Example 54

According to the procedure described in Example 4a) 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with thiophene-2-sulfonylchloride to give 125 mg5-i.-propyl-N-[6-(2-((2-thiophene)-sulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=5.41 min, [M+1]⁺=674.41, [M−1]⁻=672.46.

Example 55

According to the procedure described in Example 4a) 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with ethanesulfonylchloride to give 112 mg5-i.-propyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=5.11 min, [M+1]⁺=620.41, [M−1]⁻=618.49.

Example 56

According to the procedure described in Example 4a) 100 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with methanesulfonylchloride to give 110 mg5-i.-propyl-N-[6-(2-(methanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=4.99 min, [M+1]⁺=606.39, [M−1]⁻=605.45.

Example 57

a) To a suspension of 1 g of4,6-dichloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-pyrimidine in 20 mlof DMSO was added 1.18 g of 5-methyl-2-pyridine sulfonamide potassiumsalt and 0.5 ml of Hünig's base. The mixture was stirred at 55° C. for72 h. The dark solution was poured onto 500 ml of water and quicklyfiltered through celite. The filtrate was extracted with 500 ml and 250ml of diethyl ether. The organic layers were extracted with 100 ml ofwater. The aqueous layers were combined, acidified with 3.5 ml of aceticacid and cooled to 0° C. The precipitate that formed was collected,washed with cold water and dried under high vacuum to furnish 730 mg of5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide as a brownish powder. LC-MS: t_(R)=0.70 min, [M+1]⁺=492.43,[M−1]⁻=490.54.

b) According to the procedure described in Example 4b) 725 mg5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 2-aminoethanol to give 250 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=3.14 min, [M+1]⁺=517.54, [M−1]⁻=515.63.

c) According to the procedure described in Example 4a) 75 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with benzenesulfonylchloride to give 85 mg5-methyl-N-[6-(2-(benzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.86 min, [M+1]⁺=657.59.

Example 58

According to the procedure described in Example 4a) 75 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with thiophene-2-sulfonylchloride to give 85 mg5-methyl-N-[6-(2-(thiophene-2-sulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.79 min, [M+1]⁺=663.53.

Example 59

According to the procedure described in Example 4a) 362 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 1-propanesulfonylchloride to give 85 mg5-methyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.55 min, [M+1]⁺=623.55, [M−1]⁻=621.59.

Example 60

According to the procedure described in Example 4a) 75 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 77mg5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=5.28 min, [M+1]⁺=699.70, [M−1]⁻=697.79.

Example 61

According to the procedure described in Example 4a) 75 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with ethanesulfonylchloride to give 67 mg5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.73 min, [M+1]⁺=637.64, [M−1]⁻=635.74.

Example 62

a) A solution of 10 g of dimethyl-(o-methoxyphenoxy)malonate in 80 mldry methanol was cooled to 0° C. 6.71 g of sodium methylate was addedportionwise. To the suspension was added 2.84 g of acetamidinehydrochloride and the mixture was stirred overnight at room temperature.The solvent was removed under reduced pressure and the residue wassuspended in 100 ml of diethyl ether. The solid was filtered off, washedwith another portion of 100 ml of diethyl ether and dissolved in 50 mlof water. The pH was adjusted to 4 by adding 25 ml of glacial aceticacid. The white precipitate that formed was filtered off, washed withwater and dried to yield 5.17 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (or a tautomer)as a white powder.

b) A solution of 10.9 g of5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (or a tautomer)in 150 ml of POCl₃ was stirred at 50° C. for 72 h. The excess of POCl₃was evaporated, toluene was added to coevaporate traces of POCl₃.Eventually, an ice/water mixture was carefully added to the residue andthe pH was adjusted to 8 using 3 N sodium hydroxide solution. Themixture was further diluted with 300 ml of water and extracted with 500ml of DCM. The organic layer was separated, washed with 300 ml of water,dried over Na₂SO₄ and evaporated. The residue was dissolved again in DCMand filtered through a pad of silica gel eluting with DCM. The solventwas removed in vacuo. The resulting residue was dried to furnish 8.7 gof 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine as a beigepowder.

c) To a solution of 1.0 g of4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine in 20 ml of DMSOwas added 1.76 g of 4-tert.-butyl-benzene sulfonamide potassium salt.The mixture was stirred for 72 h at room temperature. The solution wasdiluted with 250 ml of water and extracted twice with 200 ml of diehtylether. The organic layers were extracted twice with water. The combinedaqueous layers were acidified to pH 4 with 5 ml of acetic acid andcooled to 0° C. The precipitated product was filtered off and dried invacuo to give 1.05 g of4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide as a pale beige powder. LC-MS: t_(R)=5.64 min,[M+1]⁺=462.51, [M−1]⁻=460.63.

d) According to a procedure described in Example 4b) 0.5 g4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide was reacted with 2-aminoethanol to give 560 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide. LC-MS: t_(R)=3.84 min, [M+1]⁺=487.51, [M−1]⁻=485.54.

e) According to the procedure described in Example 4a) 103 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide was reacted with thiophene-2-sulfonylchloride to give 95 mg4-tert.-butyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide. LC-MS: t_(R)=5.60 min, [M+1]⁺=633.60, [M−1]⁻=631.70.

Example 63

According to the procedure described in Example 4a) 103 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide was reacted with ethanesulfonylchloride to give 92 mg4-tert.-butyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide. LC-MS: t_(R)=5.12 min, [M+1]⁺=579.60, [M−1]⁻=577.72.

Example 64

According to the procedure described in Example 4a) 103 mg4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide was reacted with methanesulfonylchloride to give 105 mg4-tert.-butyl-N-[6-(2-(methanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulfonamide. LC-MS: t_(R)=5.12 min, [M+1]⁺=565.58, [M−1]⁻=563.69.

Example 65

According to the procedure described in Example 1a) 256 mg5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted withN-(3-hydroxy-propyl)-4-methylbenzenesulfonamide in THF in the presenceof potassium tert.-butylate to give 280 mg5-isopropyl-N-[6-(3-(4-methylbenzenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.83 min, [M+1]⁺=705.70, [M−1]⁻=703.79.

Example 66

a) According to the procedure described in Example 1g) 1.00 g5-(o-methoxyphenoxy)-4,6-dichloro-2-methyl-pyrimidine was reacted with5-methyl-2-pyridine sulfonamide potassium salt to give 1.5 g5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.57 min, [M+1]⁺=421.42, [M−1]⁻=419.46.

b) According to the procedure described in Example 4b) 1.00 g5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 2-aminoethanol to give 1.05 g5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=2.93 min, [M+1]⁺=446.51, [M−1]⁻=444.53.

c) According to the procedure described in Example 4a) 94 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 82mg5-methyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.86 min, [M+1]⁺=600.59, [M−1]⁻=598.55.

Example 67

According to the procedure described in Example 4a) 94 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with benzenesulfonylchloride to give 67.2 mg5-methyl-N-[6-(2-(benzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.68 min, [M+1]⁺=586.39, [M−1]⁻=584.42.

Example 68

According to the procedure described in Example 4a) 129 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with thiophene-2-sulfonylchloride to give 105 mg5-isopropyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=5.00 min, [M+1]⁺=684.60, [M−1]⁻=682.70.

Example 69

According to the procedure described in Example 4a) 129 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 104mg5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=5.04 min, [M+1]⁺=692.65, [M−1]⁻=690.76.

Example 70

According to the procedure described in Example 4a) 129 mg5isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with ethanesulfonylchloride to give 130 mg5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.54 min, [M+1]⁺=630.59, [M−1]⁻=628.69.

Example 71

According to the procedure described in Example 4a) 100 mg5isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with thiophene-2-sulfonylchloride to give 85 mg5-isopropyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.78 min, [M+1]⁺=683.61, [M−1]⁻=681.70.

Example 72

According to the procedure described in Example 4a) 100 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 1-propanesulfonylchloride to give 76 mg5-isopropyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.56 min, [M+1]⁺=643.65, [M−1]⁻=641.70.

Example 73

According to the procedure described in Example 4a) 100 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with ethanesulfonylchloride to give 83 mg5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.28 min, [M+1]⁺=629.63, [M−1]⁻=627.73.

Example 74

According to the procedure described in Example 4a) 100 mg5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with trifluoromethanesulfonylchloride to give 83mg5-isopropyl-N-[6-(2-(trifluoromethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=5.02 min, [M+1]⁺=669.59, [M−1]⁻=667.68.

Example 75

a) Under argon 4 g of4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (Example 1bto e) was dissolved in 40 ml of dry DMF and 3.62 g of5-methylpyridine-2-sulfonamide potassium salt followed by 2.95 ml ofHünig's base was added. The dark solution was stirred at roomtemperature for 22 h. A further portion of 0.75 g of5-methylpyridine-2-sulfonamide potassium salt was added and stirring wascontinued for 18 h. The reaction mixture was poured onto 150 ml of 10%citric acid in water and extracted four times with 150 ml of ethylacetate. The combined organic layers were washed with water, dried overMgSO₄, and evaporated. The resulting residue was suspended in 20 ml ofmethanol and 20 ml of acetone. The precipitate was collected, washedwith methanol/diethyl ether 1/1 and dried. This furnished 4.56 g of5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide as a beige powder. LC-MS: t_(R)=4.38 min, [M+1]⁺=484.58,[M−1]⁻=482.51.

b) According to the procedure described in Example 4b) 1.0 g5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 2-aminoethanol to give 950 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrmidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=3.00 min, (M+1]⁺=509.53, [M−1]⁻=507.57.

c) According to the procedure described in Example 4a) 107 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 70mg5-methyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.55 min [M+1]⁺663.56, [M−1]⁻=661.63.

Example 76

According to the procedure described in Example 4a) 107 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with thiophene-2-sulfonylchloride to give 135 mg5-methyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=4.33 min, [M+1]⁺=655.46, [M−1]⁻=653.50.

Example 77

According to the procedure described in Example 4a) 107 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with ethanesulfonylchloride to give 100 mg5-methyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=3.89 min, [M+1]⁺=601.50, [M−1]⁻=599.53.

Example 78

According to the procedure described in Example 4a) 107 mg5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide was reacted with methanesulfonylchloride to give 100 mg5-methyl-N-[6-(2-(methanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridinesulfonamide. LC-MS: t_(R)=3.72 min, [M+1]⁺=587.46, [M−1]⁻=585.50.

Example 79

According to the procedure described in Example 4a) 200 mgp-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamidewas reacted with ethanesulfonylchloride to give 220 mgp-tert.-butyl-N-[6-(3-ethansulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide.LC-MS: t_(R)=5.74 min, [M+1]⁺=619.22, [M−1]⁻=617.24.

Example 80

According to the procedure described in Example 4a) 200 mgp-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamidewas reacted with thiophene-2-sulfonylchloride to give 144 mgp-tert.-butyl-N-[6-(3-(2-thiophene-sulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide.LC-MS: t_(R)=6.06 min, [M+1]⁺=673.20, [M−1]⁻=671.24.

Example 81

100 mg4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-methanesulfonyl-5-(o-methoxyphenoxy-pyrimidin-4-yl]-benzenesulfonamidewas heated to 120° C. in 0.5 ml morpholine for 6 h. The reaction mixturewas poured onto water, acidified with citric acid to pH 4 and extractedwith ethyl acetate. The combined organic layers were dried withmagnesium sulfate and evaporated at reduced pressure to give 110 mg4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-(N-morpholino)-5-(o-methoxyphenoxy)-pyrimidin-4-yl]-benzenesulfonamide.LC-MS: t_(R)=5.43 min, [M+1]⁺=650.35, [M−1]⁻=648.45.

Example 82

According to the procedure described in Example 81) 76 mg4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-methanesulfonyl-5-(o-methoxyphenoxy-pyrimidin-4-yl]-benzenesulfonamidewas reacted with N-methyl-piperazine to give 35 mg4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-(N-(N′-methyl)-piperazinyl)-5-(o-methoxyphenoxy)-pyrimidin-4-yl]-benzene-sulfonamide.LC-MS: t_(R)=3.87 min, [M+1]⁺=663.38, [M−1]⁻=661.50.

Example 83

According to the procedure described in Example 4a) 60 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with ethanesulfonylchloride to give 45 mg5-i.-propyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=4.67 min, [M+1]⁺=564.28, [M−1]⁻=562.41.

Example 84

According to the procedure described in Example 4a) 60 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 1-propanesulfonylchloride to give 42 mg5-i.-propyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=4.88 min, [M+1]⁺=578.30, [M−1]⁻=576.43.

Example 85

According to the procedure described in Example 4a) 60 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with thiophene-2-sulfonylchloride to give 48 mg5-i.-propyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=5.06 min, [M+1]⁺=618.26, [M−1]⁻=616.39.

Example 86

According to the procedure described in Example 4a) 60 mg5-i.-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamidewas reacted with 2-propanesulfonylchloride to give 52 mg5-i.-propyl-N-[6-(2-(2-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]pyridine-2-sulfonamide.LC-MS: t_(R)=4.80 min, [M+1]⁺=578.30, [M−1]⁻=576.44.

Example 87

According to the procedure described in Example 4a) 200 mg4-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamidewas reacted with ethanesulfonylchloride to give 220 mg4-tert.-butyl-N-[6-(3-(ethanesulfonylaminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide.LC-MS: t_(R)=5.74 min, [M+1]⁺=619.22, [M−1]⁻=617.24.

Example 88

According to the procedure described in Example 4a) 200 mg4-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamidewas reacted with 2-thiophenesulfonylchloride to give 144 mg4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide.LC-MS: t_(R)=6.06 min, [M+1]⁺=673.20, [M−1]⁻=671.24.

Example 89

According to the procedure described in Example 4a) 100 mg4tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamidewas reacted with ethanesulfonylchloride to give 33 mg4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide.LC-MS: t_(R)=5.25 min, [M+1]⁺=657.33, [M−1]⁻=655.45.

Example 90

According to the procedure described in Example 4a) 100 mg4-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamidewas reacted with 2-thiophenesulfonylchloride to give 50 mg4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide.LC-MS: t_(R)=5.63 min, [M+1]⁺711.28, [M−1]⁻=709.36.

Example 91

According to the procedure described in Example 4a) 195 mg5-i.-propyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamidewas reacted with ethanesulfonylchloride to give 151 mg5-i.-propyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.13 min, [M+1]⁺=606.37, [M−1]⁻=604.51.

Example 92

According to the procedure described in Example 4a) 195 mg5-i.-propyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamidewas reacted with propanesulfonylchloride to give 60 mg5-i.-propyl-N-[6-(3-(propanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.29 min, [M+1]⁺=620.39, [M−1]⁻=618.53.

Example 93

According to the procedure described in Example 4a) 195 mg5-i.-propyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamidewas reacted with 2-thiophenesulfonylchloride to give 119 mg5-i.-propyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.49 min, [M+1]⁺=660.35, [M−1]⁻=658.41.

Example 94

According to the procedure described in Example 4a) 195 mg5-i.-propyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamidewas reacted with p-toluenesulfonylchloride to give 71 mg5-i.-propyl-N-[6-(3-(p-toluenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide.LC-MS: t_(R)=5.64 min, [M+1]⁺668.40, [M−1]⁻=666.51.

Example 95

Using methods described in the above Examples, the compounds disclosedin Table 1 can be prepared:

TABLE 1

R¹: R²:

R³:

Example 96

Using methods described in the above Examples, the compounds disclosedin Table 2 can be prepared:

TABLE 2

R¹: R²:

R³:

LIST OF ABBREVIATIONS

EA ethyl acetate CyHex cyclohexane Hex hexane DMSO dimethylsulfoxide THFtetrahydrofurane MCPBA m-chloroperbenzoic acid DMF dimethylformamide DCMdichloromethane

What is claimed is:
 1. A compound of formula I

and a pure diastereomer, a mixture of diastereomers, a diastereomericracemate, a mixture of diastereomeric racemates and meso-forms and apharmaceutically acceptable salt thereof, wherein R¹ represents aryl;aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; or heteroaryl-loweralkyl; R² represents lower alkyl; trifluoromethyl; lower alkoxy-loweralkyl; lower alkenyl; lower alkynyl; aryl; aryl-lower alkyl; aryl-loweralkenyl; heterocyclyl; heterocyclyl-lower alkyl; heteroaryl;heteroaryl-lower alkyl; cycloalkyl; or cycloalkyl-lower alkyl; R³represents phenyl; mono-, di- or tn-substituted phenyl substituted withlower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, amino, loweralkylamino, amino-lower alkyl, trifluoromethyl, trifluoromethoxy,halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl,lower alkanoyl, formyl; benzofuranyl; aryl; or heteroaryl; R⁴ representshydrogen; halogen; trifluoromethyl; lower alkyl; lower alkyl-amino;lower alkyloxy; lower alkyl-sulfono; lower alkyl-sulfinyl; loweralkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; loweralkyl-oxy-lower alkyl; hydroxy-lower alkyl-oxy-lower alkyl;hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl; amino;di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino;aryl; aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-loweralkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl;aryl-sulfinyl; heteroaryl; heteroaryl-oxy; heteroaryl-lower alkyl-oxy;heteroaryl-amino; heteroaryl-lower alkyl-amino; heteroaryl-thio;heteroaryl-lower alkyl-thio; heteroaryl-lower alkyl;heteroaryl-sulfinyl; heterocyclyl; heterocyclyl-lower alkyl-oxy;heterocyclyl-oxy; heterocyclyl-amino; heterocyclyl-lower alkyl-amino;heterocyclyl-thio; heterocyclyl-lower alkyl-thio; heterocyclyl-loweralkyl; heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl-oxy;cycloalkyl-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-loweralkyl-amino; cycloalkyl-thio; cycloalkyl-lower alkyl-thio;cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; R⁶ represents hydrogen;lower alkyl; cycloalkyl; heterocyclyl; heteroaryl; aryl;cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; heteroaryl-loweralkyl; aryl-lower alkyl; lower alkoxy-lower alkyl; loweralkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; lower alkenyl; orlower alkynyl; n represents the numbers 2, 3, 4 or 5; and X representsoxygen; sulfur; NH; CH₂ or a bond.
 2. The compound of claim 1 and apharmaceutically acceptable salt thereof, wherein X represents oxygenand R³ represents phenyl, mono-, or di-substituted phenyl substitutedwith halogen, lower alkyl, lower alkylen, lower alkyl-oxy, amino, loweralkyl-amino, lower alkyl-thio, hydroxy, hydroxymethyl or lower alkanoyl.3. A Compound of formula II

and a pharmaceutically acceptable salt thereof, wherein R¹ representsaryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; orheteroaryl-lower alkyl; R² represents lower alkyl; trifluoromethyl;lower alkoxy-lower alkyl; lower alkenyl; lower alkynyl; aryl; aryl-loweralkyl; aryl-lower alkenyl; heterocyclyl; heterocyclyl-lower alkyl;heteroaryl; heteroaryl-lower alkyl; cycloalkyl; or cycloalkyl-loweralkyl; R⁴ represents hydrogen; halogen; trifluoromethyl; lower alkyl;lower alkyl-amino; lower alkyloxy; lower alkyl-sulfono; loweralkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl;hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-loweralkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy;heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-loweralkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl;heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-loweralkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl;cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino;cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-loweralkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; R⁶represents hydrogen; lower alkyl; cycloalkyl; heterocyclyl; heteroaryl;aryl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; heteroaryl-loweralkyl; aryl-lower alkyl; lower alkoxy-lower alkyl; loweralkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; lower alkenyl; orlower alkynyl; and n represents the numbers 2, 3, 4 or
 5. 4. A compoundof formula III

and a pharmaceutically acceptable salt thereof, wherein R¹ representsaryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; orheteroaryl-lower alkyl; R² represents lower alkyl; trifluoromethyl;lower alkoxy-lower alkyl; lower alkenyl; lower alkynyl; aryl; aryl-loweralkyl; aryl-lower alkenyl; heterocyclyl; heterocyclyl-lower alkyl;heteroaryl; heteroaryl-lower alkyl; cycloalkyl; or cycloalkyl-loweralkyl; R⁴ represents hydrogen; halogen; trifluoromethyl; lower alkyl;lower alkyl-amino; lower alkyloxy; lower alkyl-sulfono; loweralkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl;hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-loweralkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy;heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-loweralkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl;heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-loweralkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl;cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino;cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-loweralkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; and R⁶represents hydrogen; lower alkyl; cycloalkyl; heterocyclyl; heteroaryl;aryl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; heteroaryl-loweralkyl; aryl-lower alkyl; lower alkoxy-lower alkyl; loweralkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; lower alkenyl; orlower alkynyl.
 5. A compound of formula IV

a pharmaceutically acceptable salt thereof, wherein R² represents loweralkyl; trifluoromethyl; lower alkoxy-lower alkyl; lower alkenyl; loweralkynyl; aryl; aryl-lower alkyl; aryl-lower alkenyl; heterocyclyl;heterocyclyl-lower alkyl; heteroaryl; heteroaryl-lower alkyl;cycloalkyl; or cycloalkyl-lower alkyl; R⁴ represents hydrogen; halogen;trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; loweralkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; loweralkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl;hydroxy-lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy;heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-loweralkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl;heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-loweralkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl;cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino;cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-loweralkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; R⁵represents hydrogen, methyl or isopropyl; R⁶ represents hydrogen; loweralkyl; cycloalkyl; heterocyclyl; heteroaryl; aryl; cycloalkyl-loweralkyl; heterocyclyl-lower alkyl; heteroaryl-lower alkyl; aryl-loweralkyl; lower alkoxy-lower alkyl; lower alkyl-thio-lower alkyl; loweralkyl-amino-lower alkyl; lower alkenyl; or lower alkynyl; and nrepresents the numbers 2 or
 3. 6. The compound according to claim 5 anda pharmaceutically acceptable salt thereof, wherein R⁴ represents loweralkyl, lower alkyloxy-lower alkyl or lower alkyloxy-lower alkyloxy-loweralkyl.
 7. The compound according to claim 5 and a pharmaceuticallyacceptable salt thereof, wherein R⁴ represents methyl.
 8. The compoundaccording to claim 5 and a pharmaceutically acceptable salt thereof,wherein R⁴ represents cycloalkyl.
 9. The compound according to claim 5and a pharmaceutically acceptable salt thereof, wherein R⁴ representsN-attached morpholinyl.
 10. The compound according to claim 5 and apharmaceutically acceptable salt thereof, wherein R⁴ represents phenyl,mono-, di- or tri-substituted phenyl substituted with lower alkyl, loweralkyloxy or methylendioxy.
 11. A compound of formula V

and a pharmaceutically acceptable salt thereof, wherein R² representslower alkyl; trifluoromethyl; lower alkoxy-lower alkyl; lower alkenyl;lower alkynyl; aryl; aryl-lower alkyl; aryl-lower alkenyl; heterocyclyl;heterocyclyl-lower alkyl; heteroaryl; heteroaryl-lower alkyl;cycloalkyl; or cycloalkyl-lower alkyl; R⁵ represents hydrogen, methyl orisopropyl; R⁶ represents hydrogen; lower alkyl; cycloalkyl;heterocyclyl; heteroaryl; aryl; cycloalkyl-lower alkyl;heterocyclyl-lower alkyl; heteroaryl-lower alkyl; aryl-lower alkyl;lower alkoxy-lower alkyl; lower alkyl-thio-lower alkyl; loweralkyl-amino-lower alkyl; lower alkenyl; or lower alkynyl; U and Vrepresent nitrogens, respectively; and W represents carbon.
 12. Thecompound according to claim 11 and a pharmaceutically acceptable saltthereof, wherein U and V represent carbons, respectively, and Wrepresents nitrogen.
 13. A compound according to formula VI

and a pharmaceutically acceptable salt thereof, wherein R¹ representsaryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; orheteroaryl-lower alkyl; R² represents lower alkyl; trifluoromethyl;lower alkoxy-lower alkyl; lower alkenyl; lower alkynyl; aryl; aryl-loweralkyl; aryl-lower alkenyl; heterocyclyl; heterocyclyl-lower alkyl;heteroaryl; heteroaryl-lower alkyl; cycloalkyl; or cycloalkyl-loweralkyl; R³ represents phenyl; mono-, di- or tn-substituted phenylsubstituted with lower alkyl, lower alkenyl, lower alkynyl, loweralkyloxy, amino, lower alkylamino, amino-lower alkyl, trifluoromethyl,trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-loweralkyl, cyano, carboxyl, lower alkanoyl, formyl; benzofuranyl; aryl; orheteroaryl; R⁴ represents hydrogen; halogen; trifluoromethyl; loweralkyl; lower alkyl-amino; lower alkyloxy; lower alkyl-sulfono; loweralkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl;hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-loweralkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy;heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-loweralkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl;heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-loweralkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl;cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino;cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-loweralkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; R⁶represents hydrogen; lower alkyl; cycloalkyl; heterocyclyl; heteroaryl;aryl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; heteroaryl-loweralkyl; aryl-lower alkyl; lower alkoxy-lower alkyl; loweralkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; lower alkenyl; orlower alkynyl; and n represents the numbers 2, 3, 4 or
 5. 14. A compoundaccording to formula VII

and a pharmaceutically acceptable salt thereof, wherein R¹ representsaryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; orheteroaryl-lower alkyl; R² represents lower alkyl; trifluoromethyl;lower alkoxy-lower alkyl; lower alkenyl; lower alkynyl; aryl; aryl-loweralkyl; aryl-lower alkenyl; heterocyclyl; heterocyclyl-lower alkyl;heteroaryl; heteroaryl-lower alkyl; cycloalkyl; or cycloalkyl-loweralkyl; R⁴ represents hydrogen; halogen; trifluoromethyl; lower alkyl;lower alkyl-amino; lower alkyloxy; lower alkyl-sulfono; loweralkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl;hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-loweralkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy;heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-loweralkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl;heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-loweralkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl;cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino;cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-loweralkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; R⁶represents hydrogen; lower alkyl; cycloalkyl; heterocyclyl; heteroaryl;aryl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; heteroaryl-loweralkyl; aryl-lower alkyl; lower alkoxy-lower alkyl; loweralkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; lower alkenyl; orlower alkynyl; and n represents the numbers 2, 3, 4 or
 5. 15. Thecompound according to any one of claims 6 to 14 and a pharmaceuticallyacceptable salt thereof, wherein R² represents lower alkyl.
 16. Thecompound according to any one of claims 6 to 14 and a pharmaceuticallyacceptable salt thereof, wherein R² represents cycloalkyl.
 17. Thecompound according to any one of claims 6 to 14 and a pharmaceuticallyacceptable salt thereof, wherein R² represents phenyl, p-tolyl, 2- or3-thienyl, 2- or 3-pyridyl, or 5-methyl-2-pyridyl.
 18. The compoundaccording to any one of claims 6 to 14 and a pharmaceutically acceptablesalt thereof, wherein R² represents naphthyl, quinolyl or biphenyl. 19.The compound according to any one of claims 1 to 14, wherein thecompound is selected from the group consisting of:p-tert.-butyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-(2-propanesulfonamido))-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-benzenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-thiophenesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-(1-propanesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,p-tert.-butyl-N-[6-(ethoxy-2-(1-butanesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-p-toluenesulfonamido)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]pyridine-2-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-methanesulfonamido)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]pyridine-2-sulfonamide,4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-methanesulfonyl-5-(o-methoxyphenoxy-pyrimidin-4-yl]-benzenesulfonamide,5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,5-i-propyl-N-[6-(2-(4-methylbenzene)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,4-tert.-butyl-N-[6-(2-(2-propane)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide,5-isoproyl-N-[6-(2-(2-thiophensulfonyl)-amino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,5-isopropyl-N-[6-(2-propanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,5-methyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,p-tert.-butyl-N-(6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,5-i.-propyl-N-[6-(ethoxy-2-thiophenesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridinesulfonamide,4-tert-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide,4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-meth-oxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide,4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide,4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide,5-i.-propyl-N-[6-(3-(propanesulfonylamino)-propoxy)-5-(o-methoxy-phenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide,5-i.-propyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxy-phenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide,and 5-i.-propyl-N-[6-(3-(p-toluenesulfonylamino)-propoxy)-5-(o-methoxy-phenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide,and a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising the compound of any one of claims 1-14 as anactive ingredient and a pharmaceutically acceptable excipient and/oradjuvant.
 21. A method of treating or ameliorating a disorder in asubject, wherein the disorder is hypertension, ischemia, vasospasm,angina pectoris, renal failure, dementia, migraine, subarachnoidalhemorrhage, Raynaud's syndrome, atherosclerosis, stomach ulcer, duodenalulcer, prostatic hypertrophy, erectile dysfunction, hearing loss,amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock,sickle cell anemia, glomerulonephritis, graucoma, diabeticcomplications, complications of transplantation, or complications ofcyclosporin, and is associated with endothelin, comprising administeringa therapeutically effective amount of the compound according to any oneof the claims 1 to
 14. 22. A method of treating or ameliorating adisorder in a subject, wherein the disorder is hypertension, ischemia,vasospasm, angina pectoris, renal failure, dementia, migraine,subarachnoidal hemorrhage, Raynaud's syndrome, atherosclerosis, stomachulcer, duodenal ulcer, prostatic hypertrophy, erectile dysfunction,hearing loss, amaurosis, chronic bronchitis, asthma, gram negativesepticemia, shock, sickle cell anemia, glomerulonephritis, graucoma,diabetic complications, complications of transplantation, orcomplications of cyclosporin, and is associated with endothelin,comprising administering a therapeutically effective amount of thecomposition according to claim
 21. 23. A process for the manufacture ofthe compound according to any one of claims 1 to 14, which processcomprises a) reacting a compound of formula VIII

 wherein R¹ represents aryl; aryl-lower alkyl; aryl-lower alkenyl;heteroaryl; or heteroaryl-lower alkyl; R³ represents phenyl; mono-, di-or tn-substituted phenyl substituted with lower alkyl, lower alkenyl,lower alkynyl, lower alkyloxy, amino, lower alkylamino, amino-loweralkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio,hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl, formyl;benzofuranyl; aryl; or heteroaryl; R⁴ represents hydrogen; halogen;trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; loweralkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; loweralkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl;hydroxy-lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy;heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-loweralkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl;heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-loweralkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl;cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino;cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-loweralkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; X representsoxygen; sulfur; NH; CH₂ or a bond; and n represents the numbers 2, 3, 4or 5, with a compound of the formula Cl—SO₂-R², wherein R² representslower alkyl; trifluoromethyl; lower alkoxy-lower alkyl; lower alkenyl;lower alkynyl; aryl; aryl-lower alkyl; aryl-lower alkenyl; heterocyclyl;heterocyclyl-lower alkyl; heteroaryl; heteroaryl-lower alkyl;cycloalkyl; or cycloalkyl-lower alkyl; or b) reacting a compound offormula IX

 wherein R¹ represents aryl; aryl-lower alkyl; aryl-lower alkenyl;heteroaryl; or heteroaryl-lower alkyl; R³ represents phenyl; mono-, di-or tn-substituted phenyl substituted with lower alkyl, lower alkenyl,lower alkynyl, lower alkyloxy, amino, lower alkylamino, amino-loweralkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio,hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl, formyl;benzofuranyl; aryl; or heteroaryl; R⁴ represents hydrogen; halogen;trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; loweralkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; loweralkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl;hydroxy-lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy;heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-loweralkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl;heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-loweralkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl;cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino;cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-loweralkyl-thio; cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; and Xrepresents oxygen; sulfur; NH; CH₂ or a bond, with a compound of formulaX

 wherein R² represents lower alkyl; trifluoromethyl; lower alkoxy-loweralkyl; lower alkenyl; lower alkynyl; aryl; aryl-lower alkyl; aryl-loweralkenyl; heterocyclyl; heterocyclyl-lower alkyl; heteroaryl;heteroaryl-lower alkyl; cycloalkyl; or cycloalkyl-lower alkyl; R⁶represents hydrogen; lower alkyl; cycloalkyl; heterocyclyl; heteroaryl;aryl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; heteroaryl-loweralkyl; aryl-lower alkyl; lower alkoxy-lower alkyl; loweralkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; lower alkenyl; orlower alkynyl; and n represents the numbers 2, 3, 4 or 5, and, ifnecessary, resolving an optically active compound into purediastereomers, a mixture of diastereomers, diastereomeric racemates, amixture of diastereomeric racemates and meso-forms and, if desired,converting a compound of formula I obtained into a pharmaceuticallyacceptable salt.
 24. A process for the manufacture of the pharmaceuticalcomposition according to claim 20, comprising mixing one or more activeingredients with the pharmaceutically acceptable excipient.